Norrin, also known as the Norrie disease protein or X-linked exudative vitreoretinopathy 2 protein, is a secreted retinal growth factor with angiogenic and neuroprotective properties. Norrin mutations are associated with the Norrie disease, familiar exudative vitreoretinopathy (FEVR), retinopathy of prematurity (ROP), and other retinal hypovascularization diseases. Despite its distinct structure from Wnt proteins, Norrin binds specifically to Frizzled 4 (Fz4), a Wnt receptor, and Lrp5/6, a Wnt co-receptor, and activates the canonical Wnt/?-catenin signaling pathway inside the cell. How Norrin activates the Wnt/?-catenin signaling pathway through its interactions with Fz4 and Lrp5/6, and how Norrin is regulated by other proteins, remain enigmatic. Here we aim to unravel the structural basis of Norrin-dependent Wnt pathway activation through the determination of the 3D structures of Norrin in complex with Fz4 and/or Lrp5/6, using a combination of X-ray crystallography, cryo-EM and biochemical analysis. We will also provide key clues to understand how Norrin is regulated by Wnt pathway regulators such as Lgr4. Understanding the structural basis of Norrin-induced Wnt pathway activation will not only reveal Norrin signaling mechanism, but also help with the development of new approaches for prevention and/or treatment of retinal hypovascularization diseases that affects about 20 million patients in the United States alone. In addition, in contras to the poor solubility of Wnt proteins due to their essential lipid modification, which prevented their practical uses in therapeutics, recombinant Norrin protein without any posttranslational modification is fully active in activating canonical Wnt signaling. Therefore, our work may also provide a structural template for designing soluble Wnt mimetics useful for stem cell biology and regenerative medicine.